Pacritinib in Vacuoles, E1 Ubiqutin-activating Enzyme, X-linked, Autoinflammatory, Somatic (VEXAS) Syndrome
- Conditions
- Interventions
- Registration Number
- NCT06538181
- Lead Sponsor
- Washington University School of Medicine
- Brief Summary
VEXAS (vacuoles, E1 ubiqutin-activating enzyme, X-linked, autoinflammatory, somatic syndrome) is a recently described disorder with severe hematologic and rheumatologic manifestations caused by somatic variants in the ubiquitin- activating enzyme gene, UBA1, that is acquired in hematopoietic progenitor cells. Patients are often debilitated by autoinflammator...
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- NOT_YET_RECRUITING
- Sex
- All
- Target Recruitment
- 15
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Patients must have UBA1 mutation with a variant allele frequency (VAF) of ≥ 2% detected on a next generation sequencing panel and have at least one of the following current or past clinical manifestation of VEXAS syndrome, as determined by the attending physician:
- skin rash
- vasculitis
- chondritis
- ocular/orbital inflammation (e.g., uveitis/iritis, episcleritis)
- genitourinary inflammation (e.g., epididymitis/orchitis)
- arthritis/arthralgias
- pulmonary inflammation (e.g., alveolitis/pleural effusion,)
- fever
- thrombosis
- splenomegaly
- hepatomegaly
- myocarditis or pericarditis
- cytopenias (defined as hemoglobin <11 g/dL, platelets < 100 X 10^9 /L, OR absolute neutrophil count <1.0 X 10^9 /L).
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Patients with VEXAS syndrome who have never been treated with a JAK-I will be eligible to enroll on study. A stable corticosteroid dose must be maintained for at least 14 days prior to start of pacritinib.
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Patients who have previously been treated with a JAK-I other than pacritinib, or who are currently being treated with a JAK-I other than pacritinib, may be eligible after a 28 day washout if either (i) their symptoms are not adequately controlled, as determined by the treating physician, or (ii) they have been unable to taper corticosteroids to an equivalent of <10 mg prednisone/day, and in the opinion of the treating physician, may benefit from a change in JAK-I. A stable corticosteroid dose must be maintained for at least 14 days prior to start of pacritinib.
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At least 18 years of age.
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ECOG performance status ≤ 3.
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Organ function as defined below:
- Total bilirubin ≤ 1.5 x IULN
- AST(SGOT)/ALT(SGPT) ≤ 3.0 x IULN
- Creatinine clearance ≥ 30 mL/min by Cockcroft-Gault
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QTcF < 480 msec.
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The effects of pacritinib on the developing human fetus are unknown. For this reason and because pacritinib was shown to be teratogenic in animal studies, women of childbearing potential and men must agree to use adequate contraception prior to study entry, for the duration of study participation, and for 3 months after completion of study treatment. Hormonal contraception is no longer considered highly effective alone as pacritinib is a CYP3A4 inducer and accelerated progesterone metabolism. The contraceptive methods considered highly effective for WOCBP who receive pacritinib are intrauterine devices, vasectomized partner, and sexual abstinence. Hormonal contraceptives (e.g., Depo-Provera) alone are not considered highly effective methods of contraception on their own when in treatment with pacritinib; such hormonal contraceptives should be combined with an additional barrier method (condom, diaphragm with spermicidal gel, or condoms with spermicides to be considered highly effective. Other highly effective contraceptive methods include intrauterine device (IUD), bilateral tubal occlusion, partner vasectomy, or total sexual abstinence. Should a woman become pregnant or suspect she is pregnant while participating in this study, she must inform her treating physician immediately.
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Ability to understand and willingness to sign an IRB approved written informed consent document or that of legally authorized representative, if applicable.
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Patients with myelodysplastic neoplasms (MDS) or plasma cell dyscrasias are eligible if they are not undergoing active treatment. Supportive care is permitted.
- Prior use of pacritinib.
- Use of another JAK inhibitor within 28 days of C1D1 of pacritinib.
- Currently receiving any other investigational agents. Patients may be eligible after 28 day washout.
- Currently receiving immunosuppressants (other than corticosteroids), disease-modifying antirheumatic drugs (DMARDs), or biologic cytokine inhibitors. Patients may be eligible after 28 day washout.
- A history of allergic reactions attributed to compounds of similar chemical or biologic composition to pacritinib.
- Concurrent use of strong CYP3A4 inhibitors or inducers. Patients may be eligible after washout period of 28 days (or 5 half-lives, whichever is shorter).
- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or uncontrolled cardiac arrhythmia.
- Pregnant and/or breastfeeding. Women of childbearing potential must have a negative serum pregnancy test within 7 days of C1D1 or negative urine pregnancy test within 3 days of C1D1.
- Known active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), or hepatitis C virus (HCV).
- Patients with latent tuberculosis. Patients must have a negative T-Spot during screening to be eligible.
- Clinically significant bleeding events within the prior 3 months unless provoked (e.g., due to trauma or surgery).
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- SEQUENTIAL
- Arm && Interventions
Group Intervention Description Expansion: Pacritinib Pacritinib Recommended phase II dose of pacritinib by mouth twice per day. Each cycle is 28 days and participants can receive up to 12 cycles of treatment. Safety Run-in: Pacritinib Pacritinib Assigned dose of pacritinib by mouth twice per day. Each cycle is 28 days and participants can receive up to 12 cycles of treatment.
- Primary Outcome Measures
Name Time Method Number of participants with dose-limiting toxicities (DLTs) Through completion of cycle 1 (estimated to be 28 days) Dose-limiting toxicities (DLTs) are adverse events defined by the protocol that occur during the DLT observation period (Cycle 1) of the study, determined to be possibly, probably, or definitely related to the study drug.
Recommended phase II dose (RP2D) Through completion of cycle 1 (each cycle is 28 days) for all treated participants The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity (DLT) during the first cycle. The recommended phase II dose (RP2D) will be less than or equal to the MTD. If the MTD is not reached, and in the opinion of the investigators, the ...
- Secondary Outcome Measures
Name Time Method Change in white blood cell count Baseline, 1 month, 3 months, 6 months, and 12 months Change in absolute neutrophil count Baseline, 1 month, 3 months, 6 months, and 12 months Change in hemoglobin Baseline, 1 month, 3 months, 6 months, and 12 months Number of participants with hematologic improvement as measured with hemoglobin Through completion of treatment (estimated to be 12 months) Using IWG 2018 criteria
Number of participants with hematologic improvement as measured with platelets Through completion of treatment (estimated to be 12 months) Using IWG 2018 criteria
UBA1 variant allele frequency Baseline, 1 month, 3 months, 6 months, and 12 months Change in absolute lymphocyte count Baseline, 1 month, 3 months, 6 months, and 12 months Number of participants with hematologic improvement as measured with neutrophils Through completion of treatment (estimated to be 12 months) Using IWG 2018 criteria
Change in platelets Baseline, 1 month, 3 months, 6 months, and 12 months Change in ESR Baseline, 1 month, 3 months, 6 months, and 12 months Change in C reactive protein (CRP) Baseline, 1 month, 3 months, 6 months, and 12 months Change in ferritin Baseline, 1 month, 3 months, 6 months, and 12 months Change in inflammatory and rheumatologic symptoms as measured by the VEXAS Disease Activity Index Baseline, 1 month, 3 months, 6 months, and 12 months Time to next treatment Through completion of follow-up (estimated to be 24 months)
Trial Locations
- Locations (1)
Washington University School of Medicine
🇺🇸Saint Louis, Missouri, United States